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Pharmacokinetic Profile of Temsirolimus With Concomitant Administration of Cytochrome P450-Inducing Medications

From Wyeth Research, Collegeville, Pennsylvania, and Cambridge, Massachusetts.

Temsirolimus is a novel inhibitor of the mammalian target of rapamycin, with antitumor activity in advanced tumors. Because temsirolimus and its metabolite, sirolimus, are cytochrome P450 (CYP) 3A4/5 substrates, the potential exists for interaction with drugs that induce CYP3A activity, including enzyme inducers and rifampin. Cancer patients received once-weekly intravenous (IV) 220 mg/m² temsirolimus with or without enzyme inducers. Coadministration with enzyme inducers decreased temsirolimus maximum plasma concentration (C_max) by 36% and increased volume of distribution by 99%. Sirolimus C_max and area under the concentration-time curve (AUC) were decreased by 67% and 43%, respectively. In healthy adult subjects, coadministration of 25-mg intravenous temsirolimus with rifampin had no significant effect on temsirolimus C_max and AUC but decreased sirolimus C_max and AUC by 65% and 56%, respectively. Rifampin decreased AUC_sum by 41%. Temsirolimus was well tolerated in both studies. If concomitant agents with CYP3A induction potential are used, higher temsirolimus doses may be needed to achieve adequate tumor tissue drug levels.

Key Words: Temsirolimus • cytochrome P450 • CYP3A • rifampin • pharmacokinetics

Address for correspondence: Joseph Boni, PhD, Director, Clinical Pharmacology, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426; e-mail: bonij{at}wyeth.com.

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